Anticipated Impact on Veterans Health Care: An estimated 2.7 million individuals in the United States were diagnosed with atrial fibrillation (AF). These individuals are estimated to have a five-fold increased risk of ischemic stroke. The emergence of target specific oral anticoagulants (TSOAC) has provided clinicians with alternatives for anticoagulation therapy. It is unknown whether the benefits of TSOACs seen in clinical trials will be maintained in a non-trial VHA population and if so, whether the improved outcomes balance the significantly higher cost of the drugs. The proposed cost-effectiveness study compares warfarin to TSOACs for a veteran population. Results will increase access to the most effective treatments for veterans and help VA policymakers develop evidence-based guidelines for AF treatment. Project Background: AF treatment focuses on the prevention of blood clots to reduce the risk of stroke. Vitamin K antagonists (e.g. warfarin) have successfully reduced the risk of stroke but the effectiveness of these methods are hampered by narrow therapeutic ranges and the need for monthly laboratory monitoring for dose adjustment to prevent over-anticoagulation and subsequent hemorrhage. Since 2010, two new classes of TSOACs, thrombin inhibitors (e.g. dabigatran) and Xa inihibitors, entered the market. Clinical trials provide good evidence that the TSOACs are either superior or not inferior to warfarin on a variety of outcomes. Initial cost-effectiveness studies based on these clinical trial results have concluded these drugs may be cost- effective. It is unknown whether the health and cost advantages of TSOACs found in clinical trials will be maintained in clinical practice since these trials enroll healthier patients and maintain better adherence. Project Objectives: We will infer causal relationships between treatments for AF, outcomes and cost. Objective 1. Estimate relationships between provider or facility-level prescribing variation and AF treatment selection controlling for process quality. Objective 2. Estimate instrumental variable (IV) and propensity score statistical models of outcomes as a function of being prescribed warfarin compared to TSOACs. Objective 3. Using the preferred specification between IV or propensity score models in Objective 2, predict health outcomes as a function of being prescribed warfarin compared to TSOACs among relevant sub- populations (e.g. age>75). Objective 4. Estimate total VA, Medicare, and VA+Medicare costs over the entire study period for patients receiving warfarin compared to TSOACs. Project Methods: The proposed project is a retrospective observational study of secondary data from patient- level administrative and claims data from VA, Medicare and Medicaid. VA pharmacy data will be used to determine whether patients with a new diagnosis of AF between 2011 and 2015 initiate warfarin or a TSOAC. Patients will be assigned to the provider that initially prescribes anticoagulation therapy. Provider prescribing patterns will be used as an instrumental variable to predict the likelihood of an individual initiating warfarin or a TSOAC, controlling for process quality (Objective 1). Residuals will be captured from the equations estimated in Objective 1 for the remaining objectives. Objectives 2 and 3 will use two-stage residual inclusion instrumental variable or propensity score models to identify the causal relationship between initiating warfarin or a TSOAC and health outcomes. Objective 4 will use similar models to predict VA and Medicare costs and determine the most cost-effective treatment.